A high-fat diet often leads to metabolic disorders such as diabetes, fatty liver disease and obesity. One lipid, however, might mitigate these effects through an unexpected signalling role in the nucleus. See Letter p.506
Lipids are best known for their integral role in biological membranes and as signalling molecules in the cytoplasm. Rarely is their importance in nuclear processes appreciated, even though it has been known for decades that lipids and the machinery that modifies them can be found in the nucleus1. On page 506 of this issue, Lee and colleagues2 explore the nuclear activities of lipids, showing that a particular species of the phospholipid phosphatidylcholine (which is a component of the food supplement lecithin) controls transcriptional programs. Their data also suggest that targeting lipid signalling in the nucleus might be of value for treating human metabolic diseases.
Structural studies3,4 have shown that phospholipids bind to the NR5A subclass of nuclear receptor. Building on these observations, Lee et al. set out to find a phospholipid ligand that activates the nuclear receptor LRH-1 (also known as NR5A2), which is important for bile-acid homeostasis5. They reasoned that such an agonist would increase bile-acid levels and reverse conditions associated with fatty liver disease. Non-alcoholic fatty liver disease can lead to hepatic steatosis, which is often associated with other metabolic disorders, including obesity, insulin resistance and type 2 diabetes.
After screening several different phospholipids in cell-based assays, the authors identified two short-chain phosphatidylcholine species that, at high concentrations (100 μM), strongly activate LRH-1. Of these, they focused on dilauroyl phosphatidylcholine (DLPC) — a species with two saturated 12-carbon fatty acyl chains (Fig. 1).
A previous structural study6 showed that bound phosphatidylcholine nestles tightly into LRH-1's closest homologue, SF-1 (also known as NR5A1). It would therefore be expected that both DLPC and a longer-chain phosphatidylcholine called DPPC would also bind to LRH-1. Intriguingly, however, Lee et al.2 report that DLPC, and not DPPC, increased LRH-1 activity. Consistent with this selective activation, they also found that a 1:1 molar ratio of DLPC, but not DPPC, could displace phospholipids bound to LRH-1. Moreover, when the authors administered these phosphatidylcholines to mice orally, DLPC elevated the levels of some, but not all, LRH-1 targets in the liver and increased the serum levels of bile acid.
Emboldened by these positive results, Lee and co-workers put DLPC to a final test to investigate whether this phospholipid might reverse diet-induced insulin resistance and fatty liver disease in mice. They fed the mice a high-fat diet (the equivalent of a continuous rich, greasy human diet) for nearly four months, to make them fat and diabetic. The authors then gave these metabolically challenged animals an oral dose of DLPC (100 milligrams per kilogram of body weight per day) for another three weeks.
The physiological effects of DLPC were truly impressive, reversing the metabolic problems commonly observed with a high-fat diet and obesity. Compared with control animals, glucose homeostasis and insulin signalling were substantially improved, and the histological hallmarks of fatty liver significantly diminished.
This paper2 firmly establishes the beneficial actions of DLPC. But how does this trace component of lecithin perform its metabolic magic? The authors posit that DLPC functions as a natural ligand for LRH-1. In favour of this hypothesis, they discovered that almost all of DLPC's therapeutic benefits disappear when LRH-1 is genetically ablated in the liver. Coupled with their cellular data, this observation makes for a compelling case that DLPC is a ligand for LRH-1. But there is ample room for sceptics and alternative models, especially given the extremely high levels of DLPC that Lee and colleagues used in their cellular studies. For example, DLPC might target LRH-1 indirectly, either by triggering a signalling cascade or by serving as a metabolic precursor for the 'real' lipid ligand of LRH-1.
The work also raises other questions, beginning with the basic one of how DLPC enters the cell. Could a dedicated flippase enzyme or a transporter facilitate its entry? And once inside the cell, how does it reach the nucleus? Is it shuttled there by specialized phospholipid-transfer proteins? If DLPC does make its way into the nucleus to bind LRH-1, could existing synthetic ligands7 mimic its cellular and physiological effects?
Equally perplexing are the selective effects of DLPC compared with DPPC, which share identical head groups and differ only in their acyl-chain length (12 and 16 carbons, respectively; Fig. 1). How does this difference affect these phospholipids' binding affinities and change receptor activation? If we assume, on the basis of structural studies, that the head groups are similarly positioned at the 'mouth' of the ligand-binding pocket, what path do the buried acyl chains take to account for the vastly different activities observed for DLPC and DPPC? Such questions merely underscore both the challenge and the mystery of lipid signalling in the nucleus.
What emerges from Lee and colleagues' work2 is that, surprisingly, phosphatidylcholines reverse some of the consequences of a high-fat diet in rodents. Consistent with this is the earlier finding8 that 1,2-dilinoleoyl-sn-glycero-3-phosphocholine — the major component in soya bean lecithin — was partially effective in treating fatty liver disease (note that this phosphatidylcholine species is also abbreviated to DLPC but differs from the DLPC used in the current study2). And, more recently, it has also been reported9 that injection of another phosphatidylcholine called POPC into the portal vein decreases hepatic steatosis in mice, possibly by binding and activating another nuclear receptor, PPARα. On the basis of this evidence2,8,9, dietary phosphatidylcholines could certainly offer a new option for treating human metabolic disorders. But regardless of whether phospholipids can mitigate decades of bad eating habits, this study illustrates a potentially powerful role for phospholipid signalling in the nucleus.
Irvine, R. F. Nature Rev. Mol. Cell Biol. 4, 349–361 (2003).
Lee, J. M. et al. Nature 474, 506–510 (2011).
Krylova, I. N. et al. Cell 120, 343–355 (2005).
Ortlund, E. A. et al. Nature Struct. Mol. Biol. 12, 357–363 (2005).
Lee, Y.-K. & Moore, D. D. Front. Biosci. 13, 5950–5958 (2008).
Sablin, E. P. et al. Mol. Endocrinol. 23, 25–34 (2009).
Whitby, R. J. et al. J. Med. Chem. 54, 2266–2281 (2011).
Lieber, C. S. et al. Nutr. Res. 27, 565–573 (2007).
Chakravarthy, M. V. et al. Cell 138, 476–488 (2009).
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